The overall purpose of the work proposed is to better understand the physical and physiological factors that affect the BOLD (blood oxygenation level dependent) signals detected in functional magnetic resonance imaging (fMRI). FMRI is a very important addition to the methods available for non-invasive mapping of the human brain, and is being widely used in clinical medicine as well as in basic studies of cognition. Although there is general agreement about how BOLD signals originate, there are still many features of the BOLD effect that are uncertain, and the influence of several factors is unknown, especially for so-called event-related fMRI. These deficits in understanding limit our ability to interpret fMRI data quantitatively. Furthermore, we do not understand well what limits the sensitivity of fMRI in practice, nor what gains may be possible as higher field strength magnets become more widely available. In the next phase of this grant we will quantify the effects of several technical and physical factors that modify the shape and amplitude of transient event-related fMRI responses. In both a rat model of somatosensory activation and human cortex, we will quantify the effects of field strength, pulse sequence, stimulation parameters, and intrinsic blood susceptibility, on the latency, magnitude and duration of event related responses, and verify these may add non-linearly when closely spaced. We will also quantify the effects of several physiological and pharmacological factors that commonly vary in humans subjects on the event-related responses, including the effects of altered basal flow, mild hypoglycemia, reduced hematocrit, levels of blood carbon monoxide, nicotine and caffeine, and estrogen, on the characteristics of the event-related BOLD signal. In order to clarify the validity of current models that are used to relate BOLD signals to underlying metabolic and physiological changes, we will measure the relationship between cerebral blood volume and flow in a rat model with graded hypercapnia and with neural stimulation, Finally, we will quantify and characterize the sources of noise that affect the fMRI signal. We will measure the contributions to signal variance that may arise from cardiac, respiratory, movements and vasomotor effects, and assess how these affect the fMRI signal/noise ratio, for different choices of technical factors including field strength, pulse sequence, echo time, and spatial resolution. These studies will further our efforts to understand and interpret data provided from fMRI better, and provide important insights into how to improve the quality of information obtainable by fMRI in diverse applications at different field strengths.